Stain-resistant chemicals increase brain protein levels in mice.

Apr 03, 2009

Johansson, N, P Eriksson, and H Viberg. 2009. Neonatal exposure to PFOS and PFOA in mice results in changes in proteins which are important for neuronal growth and synaptogenesis in the developing brain. Toxicological Sciences doi:10.1093/toxsci/kfp029.

Synopsis by Paul Eubig, DVM and Wendy Hessler

David's digits/Flickr

Perfluorinated compounds PFOS and PFOA, given to mice at an age that corresponds to rapid brain growth in infants, alter levels of several proteins important for normal brain development. This study provides evidence for another chemical that can affect brain proteins necessary to form synapses and carry messages between nerve cells. The two PFCs are widspread in the environment. 



The human brain rapidly grows before and after birth. During this dramatic time of development, the nerve cells (neurons) elongate and actively make and break connections to provide the lifelong blueprint for brain function.

Rapid development in the brain occurs within the first month of life in mice, peaking at 10 days of age, while in humans it spans from the third trimester of pregnancy through age two. This period is often called the “brain growth spurt.”

A developing brain is more vulnerable to toxic insults than the brain of an adult. Environmental contaminants such as PCBs, PBDEs, and mercury can alter neuron functioning, often when a fetus is still in the womb. This can result in long-lasting changes to the brain.

Perfluorinated compounds (PFCs) -- such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) -- can repel both water and fat, making them valuable barriers against stains and moisture. The chemicals are used in clothing, carpeting, upholstery, floor and car waxes, firefighting foams, and even in the lining of food containers (pizza boxes and microwave popcorn bags).

Given their use, it is not surprising that PFCs are found in much greater levels indoors than out. PFCs have been found in up to 98 percent of people sampled in the US in the late 1990s; decreases were seen in 2004 after manufacturers started phasing them out of ordinary products.

The same properties desired in consumer products make them hazardous elsewhere. The persistent compounds can accumulate in humans and animals. They are incredibly long-lived and resist breakdown in people, animals and the environment.

Unfortunately, humans have a harder time eliminating these substances from their bodies than other animal species studied. A single exposure to perfluorinated compounds remains in the body for years, compared to days, weeks and months for rodents, monkeys or other mammals.

PFCs can cross the placenta from the mother to the fetus, and they are also found in breast milk. Young children and toddlers may be exposed, too. They crawl on floors and eat and breath house dust, which contains the chemicals.

Research suggests PFCs behave in a similar way as persistent organic pollutants (POPs). In animal studies, PFOS and PFOA can affect thyroid hormones and the neurological system, sometimes changing behavior.

Prior studied report behavior and brain protein changes after exposire to PFCs and flame retardants.  The same research group found PFOS and PFOA altered behavior in very young mice: they were less likely to explore and were less able to adjust to a new open area as quickly as untreated mice (Johansson et al. 2008). Other studies find exposure of newborn rodents to flame retardants -- called PBDEs -- can increase the brain protein CaMKII in the hippocampus (Viberg et al. 2008).

Because children are exposed to perfluorinated compounds before and after birth, it is important to know if these chemicals can affect the developing brain.

What did they do?

This study looks for changes in brain proteins that may account for the "deranged spontaneous behavior" including hyperactivity observed in earlier experiments exposing young mice to perfluorinated chemicals.

Researchers gave 10-day-old mice a single, oral dose of either 11.3 mg/kg of PFOS or  8.7 mg/kg of PFOA.

This stage of brain development is similar to the period of rapid brain growth in humans. The levels respresent doses from prior studies that caused behavioral effects. The chemicals were chosen because other PFCs often degrade to the highly persistent PFOS and PFOA.

Four proteins were measured in two regions of the brain --  the hippocampus, important for learning and memory, and the cerebral cortex, important for learning, movement, organizing and planning.

Protein levels in the treated mice were compared to levels in mice that did not receive the chemicals. The four proteins -- CaMKII, GAP-43, synaptophysin, and tau -- are important for growing neural connections and for communication among brain nerve cells.

One dose of PFOA and PFOS significantly increased levels of proteins in the newborn mice brains, when compared to untreated mice. The  compounds acted differently in the separate brain regions.

Levels of all four proteins were elevated in the hippocampus. PFOS affected all but tau while PFOA affected all four of the protiens. Levels increased from about 20 percent for GAP-43 to almost 60 percent for CaMKII and 90 percent for tau.

In the cerebral cortex, both compounds affected only two of the proteins -- synaptophysin and tau. Levels were elevated from about 60 percent to 140 percent.

However, more may not necessarily be better. In the developing brain a precise balance of chemical messengers is vital for normal growth and formation of connections. Too much or too little of any protein can change normal development of the brain.

What does it mean?

These findings suggest that the brain is sensitive to PFOS and PFOA during development. The hippocampus may be more sensitive than the cerebral cortex, but both regions of the brain were clearly affected.

Changes in protein levels could have lifelong effects because they can alter the way synapses are formed and the way they function throughout life. The exposures increased the proteins at a time during normal development when their levels would be declining, according to the results.

This paper also adds more evidence to a growing list of known chemicals that can affect brain chemistry in similar ways, especially if exposure occurs soon after birth during the period of rapid development. The authors say "it is worth noting that these proteins are affected after neonatal exposure to PFOA, PBDE 203, 206, 209, and ketamine, at doses where we have observed functional impairments in adult mice."

Because children can be exposed to perfluorinated compounds before and after birth, this study suggests it will be important to determine if typical household exposure to these chemicals can affect the development of the brain in children. The growing brain can be quite unforgiving if normal development is impaired, with life-long changes sometimes occurring.

In people, abnormal brain protein structure (such as tau) is a hallmark of both Parkinson's disease and Alzheimers disease. Both diseases manifest later in life and their causes are unknown. While this study cannot possibly link the early life exposures to the disease, the researchers speculate that based on results from animal studies "it is possible that early exposure to certain PFCs can affect processes linked to neurodegeneration, with consequences for cognitive function."

The amounts of PFOS and PFOA used in this study were higher than levels to which humans are ordinarily exposed. However, there are two reasons why that is not necessarily a weakness of the study.

First, it is known that animals such as mice and rats clear perfluorinated compounds more quickly from their bodies than humans, so a larger amount must be given to them to mimic the degree of human exposure. Second, studies such as this are intended to find what types of changes a chemical causes. That information is then used to identify the types of changes for which exposed humans should be evaluated.

It is important to note that manufacturers of perfluorinated compounds in the United States are gradually phasing out the use of many perfluorinated compounds. However, given the long persistence of these chemicals in the environment, they will be with us for years to come, so it is still important to study their effects on health.

Johansson, N, A Fredriksson, and P Eriksson. 2008. Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioral defects in adult mice. Neurotoxicology 29(1):160-169.

Perfluorinated compounds. 2007. National Report on Human Exposure to Environmental Chemicals, Centers for Disease Control and Prevention.

Perfluorooctanoic Acid (PFOA). US Environmental Protection Agency.

Spotlight on polyfluorochemicals. 2007. National Report on Human Exposure to Environmental Chemicals, Centers for Disease Control and Prevention (PDF).

Viberg, H, W Mundy and P Eriksson. 2008. Neonatal exposure to decabrominated diphenyl ether (PBDE 209) results in changes in BDNF, CaMKII and GAP-43, biochemical substrates of neuronal
survival, growth, and synaptogenesis
. Neurotoxicology 29:152-159.

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